The aim of this research is to identify and characterize genes whose activity is involved in the progression of cells from the normal to the neoplastic phenotype in mice and humans. Genes that specify sensitivity to promotion of neoplastic transformation, by tumor-promoting phorbol esters in mouse epidermal JB6 cells, have now been cloned. By carrying out a sib selection on a genomic plasmid library of DNA from promotion-sensitive cells, two independently active clones containing active segments of l.l and 3.8 Kb, and designated pro-1 and pro-2, have been isolated. The gene, pro-1, is structurally unrelated to any of 11 of the known oncogenes. This should not be surprising if it is the case that oncogenes are involved in maintenance of the tumor cell phenotype, while pro genes specify events in induction of neoplasia. In addition, a novel transforming activity not detectable after DNA transfection into NIH 3T3 cells has been identified in the DNA of tumor cells derived from JB6 cells by TPA exposure. The future course of this investigation of mouse genes will focus on using unique pro gene probes to determine whether the basis for resistance of promotion-resistant JB6 cells or tumor promotion-resistant rodents (in vivo) involves altered structure or altered expression of pro genes. The functions of pro genes will be sought. The nature of the interaction between pro genes, which may function only when their expression is induced by tumor promoters, and transforming genes, which may be expressed constitutively once induced or activated, will be investigated. Currently a biological assay is being developed for measuring the activity of the dominant gene that specifies the human cancer-prone trait Basal Cell Nevus Syndrome (BCNS). This assay will be used to clone the BCNS gene.